The long-term goals of this research are to understand the mechanisms for the decline in hippocampal-dependent memory function during aging. The incidence of Alzheimer s disease is projected to nearly quadruple in the next 50 years with the greatest prevalence in women. Importantly, estrogen treatment can delaying the progression of memory loss associated with aging and Alzheimer s disease. However, little is known concerning which of the many estrogen associated effects on brain function are important for memory. The discovery of several different estrogen receptors (Ers) within the hippocampus makes this challenge more formidable. Recent studies suggest that age- related memory impairment is due to changes in the threshold for synaptic modification thought to underlie memory storage processes. In turn, threshold changes are linked to altered Ca2+ homeostasis during aging. Interestingly, the influence of estradiol (E2) on Ca2+ homeostasis is diametrically opposed to the changes observed in aged memory impaired animals. The proposed studies test the hypothesis that E2 effects on memory are due to changes in the susceptibility to synaptic modification as a result of altered Ca2+ homeostasis processes. The proposal has three specific aims. First we will characterize the effects of E2 replacement, at physiologically relevant doses, on tasks that are sensitive to hippocampal-dependent memory function. In addition, these studies will employ female Eralpha knockout mice to determine whether Eralpha activation is involved in E2 mediated effects on memory. Second, we will test the hypothesis that E2 effects on memory are mediated by changes in the thresholds for synaptic plasticity. It is predicted that the frequency-response function for synaptic plasticity is transformed by E2 replacement due to a shift in the threshold for synaptic modification, and memory function will correlate with synaptic plasticity. Thirdly, we will test the hypothesis that E2 mediated changes in synaptic modification are due to nongenomic mechanisms that rapidly regulate Ca2+ homeostasis and cell excitability. For these studies, the effect of E2 on the Ca2+-dependent processes including synaptic plasticity will be examined in the hippocampal slice. We believe that the results of our experiments will add significantly to our knowledge concerning the regulation of synaptic function across the life span and provide a basis for understanding the mechanism for estrogen s effects of memory.